Flexible Macromolecular Docking

结合，结合完全灵活的多肽、环或蛋白质末端与相对结构化的部位的结合 在其分子伴侣的表面上是一种普遍存在的暂态大分子 调节大部分识别和信号传递的交互作用是级联的。在跨越一个 广泛的亲和力，这种互动统一涉及结构化的和非结构化的 合作伙伴可以在彼此不存在的情况下作为独立实体存在，并且仅关联 在一段有限的时间内导致构象变化、招募或解离 其他蛋白质进出复合体，以及下游通路的激活或抑制。 蛋白质-多肽相互作用的合成肽调节剂往往很有前途 治疗癌症、炎症和内分泌紊乱的候选药物。 尽管瞬时蛋白质-多肽相互作用对生物医学研究至关重要 和治疗发现，这些复合体中只有一小部分服从于 实验结构确定。因此，只有准确的多肽对接才可能导致 在对蛋白质-多肽相互作用的结构理解上取得突破。但对于更长的多肽来说 超过6-8个氨基酸，构象搜索的压倒性的规模和复杂性 空间，由于诱导匹配、低效，在结合部位表示中不可避免的不准确 或抽样不够彻底，计分函数误差累积，妨碍 通过计算方法准确确定多肽结合的位置和相互作用。 目前的建议打算极大地扩大多肽和蛋白质大小的范围 通过全局构象可以实现哪种精确的复杂几何预测 优化。这一进展将通过追求两个具体目标来实现：(目标1)发展 以及利用化学场增强技术优化可靠的多肽对接程序 随机整体中的结合位表示和改进的熵计算 在内部坐标中进行构象搜索；以及(目标2)已开发的议定书的扩展 到特定的生物项目，通过实验验证预测的几何形状和 多肽变种。目标1中提出的创新战略包括使用新的力场， 化学场对结合位表示的富集化和最佳化 用于诱导配合的口袋的构象扩展。目标2的目标包括络合物 A、B类GPCRs及其蛋白和多肽调节剂及其与G蛋白αI的相互作用 用全球环境基金的多肽。 这项提案的目标的实现将导致在灵活性方面取得突破性进展 大分子对接。它将产生有价值的软件工具、协议和共享资源 对于生物界来说。它还将导致发现新的多肽调节剂 重要的治疗、免疫和诊断目标。

The binding of a fully flexible peptide, loop, or terminus of a protein to a relatively structured site on the surface of its molecular partner is a prevalent type of a transient macromolecular interaction that mediates the majority of recognition and signaling cascades. While spanning a wide range of affinities, such interactions uniformly involve a structured and an unstructured partner that may exist as independent entities in the absence of one another and only associate for a limited period of time resulting in conformational changes, recruitment or dissociation of other proteins to/from the complex, and activation or inhibition of the downstream pathways. Synthetic peptide modulators of protein-peptide interactions are frequently promising therapeutic candidates in cancer, inflammation and endocrine disorders. Despite the critical importance of transient protein-peptide interactions for biomedical research and therapeutic discovery, only a small fraction of these complexes are amenable to experimental structure determination. Therefore, only accurate peptide docking may lead to a breakthrough in structural understanding of protein-peptide interactions. Yet for peptides longer than 6-8 amino acids, the overwhelming size and complexity of the conformational search space, the inevitable inaccuracies in the binding site representation due to induced fit, inefficient or insufficiently thorough sampling, and accumulation of scoring function errors prohibit the accurate determination of peptide binding poses and interactions by computational methods. The present proposal intends to dramatically expand the range of peptide and protein sizes for which accurate complex geometry prediction can be achieved by global conformational optimization. This advance will be made by pursuing two Specific Aims: (Aim 1) Development and optimization of a reliable peptide cross-docking procedure using chemical field-enhanced binding site representations and improved entropy calculations in the stochastic global conformational search in internal coordinates; and (Aim 2) Extension of the developed protocol to specific biological projects with experimental validation of the predicted geometries and peptide variants. The innovative strategies proposed in Aim 1 include using a new force field, the enrichment of binding site representations with chemical fields, and the optimal conformational expansion of the pocket for induced fit. The targets of Aim 2 include complexes of Class A and B GPCRs with their protein and peptide modulators and G-protein αi interactions with GEF peptides. The attainment of the aims of this proposal will lead to breakthrough advances in flexible macromolecular docking. It will result in valuable software tools, protocols and shared resources for the biological community. It will also lead to discovery of new peptide modulators of important therapeutic, immune, and diagnostic targets.